Campylobacter jejuni is a leading cause of foodborne human gastroenteritis in the United States, with an incidence rate of 13.6 diagnosed cases per 100,000 individuals. As many infections go undiagnosed, it is predicted that the actual incidence is much higher, with estimates of approximately 1.3 million cases of campylobacteriosis in the United States annually, primarily arising from poultry, which serves as a natural reservoir for C. jejuni. Campylobacteriosis is characterized by mild to severe, bloody diarrhea, abdominal pain, and fever occurring two to five days following infection. Campylobacter infection can also lead to Guillain- Barr? syndrome (GBS), a paralytic illness resulting from the immune system attack on the peripheral nervous system. Research to uncover factors of C. jejuni that contribute to development of human campylobacteriosis has been hindered by lack of an animal model that replicates the clinical features of human disease. The chicken model, widely used in the field, is not a disease model, as chickens are a natural primary reservoir for Campylobacter species. For animal models that mimic human disease, much work has centered on immunodeficient mice, including strains lacking MyD88, IL-10 or subunits of NF-kB. These are sub-optimal as models of human disease because colonization does not generally lead to clinical signs of disease consistent with those of human infection, such as gastroenteritis and diarrhea. In contrast, infections in the young ferret closely mimic human infection, including development of diarrhea containing frank blood, and resistance to disease upon subsequent re-infection. Little is understood, however, about host and microbial mechanisms that underlie campylobacteriosis in the ferret model. For this exploratory proposal, a broad approach to uncover physiological and genetic factors contributing to C. jejuni infection in ferrets will be taken, combining transcriptomics, genetics, meta-genomics, and metabolomics. This approach has been applied to understand C. jejuni commensal association with the chicken gastrointestinal tract, leading to discovery of important colonization determinants and many new regulatory elements including potential non-coding RNAS. Adopting this strategy to study a disease model will provide unprecedented insight into important host-pathogen interactions relevant to C. jejuni pathogenicity. The proposed work for this exploratory proposal has the following two aims: Specific aim 1. Identify C. jejuni determinants and correlates of pathogenicity in the ferret model using transcriptomic and genome-wide mutagenesis studies Specific aim 2. Determine the ferret response to Campylobacter jejuni infection using transcriptomic, metagenomic, and metabolomic studies